Low-Molecular-Weight Phosphatase B (LMW-MPtpB) inhibition as a strategy to identify new drug candidates against tuberculosis

The last WHO Global TB Report estimated that 10 million people worldwide fell ill with tuberculosis (TB) in 2019. The resistance to anti-TB drugs is a global health problem that interferes with the progress of TB eradication. Hence, novel and more effective anti-TB drugs acting on unexplored targets are needed to contrast the resistance phenomenon and the progressive loss of antibiotic efficacy, and to improve the current therapies. Mycobacterium tuberculosis (Mtb) secretes two Low- Molecular-Weight Phosphatases (LMW-PTPs), MPtpA and MPtpB, inside the cytoplasm of host macrophages. These enzymes are indispensable for the intracellular survival of Mtb because they interfere with the host immune response, thus allowing bacteria to evade the immune system. For this reason, MPtpA and MPtpB were validated as promising targets for the development of innovative antitubercular agents. Recent computational studies defined a new pharmacophore model, which was applied to screen two commercial databases, Vitas-M and Enamine. These virtual screening experiments led to the selection of 8 molecules for MPtpB inhibition (see Figure 1). The biological data will be discussed, along with preliminary investigations on the most promising candidates.